HIV-associated neuropathies have become the main neurological complications of HIV infection affecting quality of life and limiting viral suppression strategies. The mechanisms underlying these neuropathies are unknown and there are currently no effective therapies. Recently we developed in vitro models of antiretroviral toxic neuropathy (ATN) and distal sensory polyneuropathy (DSP) associated with HIV infection per se. We also showed that certain immunophilin ligands are neuroprotective against nucleoside analogue reverse transcriptase inhibitor (NRTI) induced neurotoxicity. Immunosuppressive actions of immunophilin ligands are mediated by binding to calcineurin and nonimmunosuppressive analogues of immunophilin ligands have been developed. These compounds lack binding to calcineurin and have been shown to be neuroprotective in a variety of neuronal injury paradigms. We propose to use one such compound, GPI-1485 (Guilford Pharmaceuticals) to examine the neuroprotective potential in in vitro models of ATN and DSP. We will examine the underlying mechanism of potential neuroprotection by GPI-1485 against NRTI and HIV envelope protein-induced neurotoxicity in dorsal root ganglion sensory neurons. These studies will establish the rationale for the animal studies and clinical trials that are part of this application. In addition to the GPI-1485, which is an FKBP-ligand (FK506 binding protein) we will examine the potential neuroprotection by cyclophilin D analogues that are nonimmunosuppressive because they lack binding to calcineurin. HIV-associated neuropathies provide an important avenue to develop neuroprotective strategies in contrast to other neuropathies. The incidence of neuropathy is high enough that co-administration of a neuroprotective compound along with NRTIs may be feasible and permit unhindered viral suppression strategies. Furthermore these compounds have been shown to have neurotrophic actions in other neuronal injury paradigms and may be useful for HIV infected individuals who have already developed neuropathy.